U.S. patent application number 09/827785 was filed with the patent office on 2001-08-16 for acellular pertussis vaccine with diphthriae-and tetanus-toxoids.
This patent application is currently assigned to SmithKline Beecham Biologicals s.a.. Invention is credited to Florent, Patrick, Stephenne, Jean, Vandecasserie, Christian.
Application Number | 20010014331 09/827785 |
Document ID | / |
Family ID | 26310357 |
Filed Date | 2001-08-16 |
United States Patent
Application |
20010014331 |
Kind Code |
A1 |
Florent, Patrick ; et
al. |
August 16, 2001 |
Acellular pertussis vaccine with diphthriae-and tetanus-toxoids
Abstract
This invention relates to a diphtheria, tetanus and pertussis
vaccine comprising a low dose of each of diphtheria toxoid (D),
tetanus toxoid (T), pertussis toxin (PT), filamentous
haemagglutinin (FHA) and pertactin (69K). The vaccine maintains an
ability to prevent pertussis while showing exceptionally low
reactogenicity. Combination vaccines comprising additional antigens
are also provided.
Inventors: |
Florent, Patrick; (Brussels,
BE) ; Stephenne, Jean; (Rixensart, BE) ;
Vandecasserie, Christian; (Lasne, BE) |
Correspondence
Address: |
GLAXOSMITHKLINE
Corporate Intellectual Property - UW2220
P.O. Box 1539
King of Prussia
PA
19406-0939
US
|
Assignee: |
SmithKline Beecham Biologicals
s.a.
|
Family ID: |
26310357 |
Appl. No.: |
09/827785 |
Filed: |
April 6, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09827785 |
Apr 6, 2001 |
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09284887 |
May 27, 1999 |
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09284887 |
May 27, 1999 |
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PCT/EP97/06180 |
Nov 4, 1997 |
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Current U.S.
Class: |
424/184.1 ;
424/130.1; 424/204.1 |
Current CPC
Class: |
A61K 39/05 20130101;
Y02A 50/466 20180101; C12N 2730/10134 20130101; A61K 39/08
20130101; A61K 2039/70 20130101; Y02A 50/30 20180101; A61K 39/0018
20130101; A61K 39/12 20130101 |
Class at
Publication: |
424/184.1 ;
424/204.1; 424/130.1 |
International
Class: |
A61K 039/00; A61K
039/12; A61K 039/395 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 7, 1996 |
GB |
9623233.5 |
Claims
What is claimed is:
1. A vaccine composition comprising diphtheria (D), tetanus (T) and
acellular pertussis (Pa) antigens and an adjuvant, wherein wherein
the concentration of D per 0.5 ml dose of bulk vaccine does not
exceed 5 Lf and is preferably 1-4 Lf, more preferably about 2 Lf;
the concentration of T per 0.5 ml dose of bulk vaccine does not
exceed 10 Lf and is preferably 2.5-7.5 Lf, more preferably about 5
Lf and the Pa component comprises PT (pertussis toxoid), FHA
(filamentous hemagglutinin) and pertactin (69 K) wherein the
concentration of PT per 0.5 ml dose of bulk vaccine does not exceed
10 ug and is preferably 2-10 ug, more preferably about 8 ug; the
concentration of FHA per 0.5 ml dose of bulk vaccine does not
exceed 10 ug and is preferably 2-10 ug, more preferably about 8 ug;
and the concentration of 69 K does not exceed 4 micrograms per 0.5
ml dose of bulk vaccine and is preferably in the range 0.5 ug to 3
ug, more preferably 2 to 3 ug, more preferably approximately 2.5 ug
per 0.5 ml dose of bulk vaccine.
2. A vaccine composition according to claim 1 having the
composition: PT (8 ug), FHA (8 ug), 69 K (2.5 ug), D (2 Lf) and T
(5 Lf) per 0.5 ml dose of bulk vaccine.
3. A vaccine composition according to any one of claims 1 or 2
which additionally comprises one or more additional antigens.
4. A vaccine composition according to claim 3 wherein an additional
antigen is hepatitis B surface antigen.
5. A vaccine composition according to claim 4 wherein the hepatitis
B surface antigen is the S-antigen of HBsAg.
6. A vaccine composition according to claim 3 or claim 4 wherein an
additional antigen is present which provides immunity against one
or more of Hib, polio or hepatitis A infection.
7. A vaccine composition according to any previous claim wherein
the adjuvant used in the formulation comprises aluminium
hydroxide.
8. A vaccine composition according to any previous claim wherein
the adjuvant used in the formulation comprises aluminium
phosphate.
9. A method of preventing disease in children or adolescent or
adult subjects, which comprises vaccinating the subjects with a
vaccine composition according to any one of claims 1 to 8.
Description
[0001] The present invention relates to new vaccine formulations,
comprising a low dose of the 69 kda outer membrane protein of
Bordetella pertussis (hereinafter termed `69 K` or `69 K antigen`
or pertactin, disclosed in European Patent 0 162 639. Recombinant
69 K (P69) has been described by N F Fairweather et al, Symposium
On Pertussis (Bethesda), Sep. 26-28 1990). The invention in
particular relates to a vaccine comprising more than one antigen,
especially a multivalent vaccine, that is: a vaccine for the
amelioration or treatment of more than one disease state, in which
a low dose of 69 K is present. The present invention also relates
to the production and use of such vaccines in medicine.
[0002] It is known that 69 K is an important component of acellular
pertussis vaccines (Pa vaccines) for the effective prevention of
pertussis.
[0003] A study on the dose responses of 5 acellular pertussis
vaccines in healthy adults was published by the US National
Institutes of Health (NIH) in May 1996 by Keitel, W. et al.
[0004] 69 K-containing vaccines including `trivalent` vaccines
comprising antigens against diphtheria (D), tetanus (T) and
pertussis (Pa) have been described in clinical trials conducted in
Italy and Sweden and are marketed [for example under the Trade Mark
INFANRIX-DTPa (SmithKline Beecham Biologicals)]. Typically the
pertussis component of such vaccines comprises pertussis toxin
(PT), filamentous haemagglutinin (FHA) and 69 K. In INFANRIX-DTPa
(Trade Mark) the amounts of D:T.PT.FHA:69 K are typically 25 Lf: 10
Lf: 25 ug:25 ug:8 ug per 0.5 ml dose of bulk vaccine.
[0005] Other multivalent vaccines comprising 69 K are also known,
for example vaccines comprising an antigen against hepatitis B and
antigens against diphtheria, tetanus and pertussis (Hep B, DTPa)
were described in WO 93/24148. In such formulations the quantity of
D.T:PT.FHA:69 K was given as 25 Lf: 10 Lf: 25 ug:25 ug:8 ug per 0.5
ml dose of bulk vaccine.
[0006] It has now been found that a diphtheria, tetanus and
pertussis vaccine containing a low dose of each of diphtheria
toxoid (D), tetanus toxoid (T), PT, FHA and 69 K (herein such a low
dose formulation is abbreviated to a dtpa vaccine) maintains an
ability to prevent pertussis (and is highly effective in this
respect) while having the advantage of showing exceptionally low
reactogenicity Within the limits described herein such vaccines are
safe when administered to human subjects and induce rapid
protection against infection. In combination vaccines comprising
dtpa and other antigens it has been found that there is no
interference, i.e. such vaccines show no loss of immunogenicity,
and are effective when administered to humans.
[0007] In particular the vaccines of this invention are suitable
for administration to children as a booster following prior
administration of one or more (typically up to about 3) doses of a
vaccine comprising a higher dose of D, T, and Pa antigens such as
the INFANRIX-DTPa vaccine described above (D:T:PT:FHA:69 K=25 Lf:
10 Lf: 25 ug:25 ug:8 ug per 0.5 ml dose of bulk vaccine). The
vaccines of this invention are also of great value for
administration to adults and adolescents.
[0008] Accordingly the present invention provides a vaccine
composition comprising a low dose of each of the antigens D, T, PT,
FHA and 69 K (i.e. a dtpa vaccine composition). It will be
understood that the vaccine composition of the invention is
formulated with a suitable carrier or adjuvant.
[0009] By dtpa vaccine or dtpa vaccine composition is meant a dose
wherein the concentration of D per 0.5 ml dose of bulk vaccine does
not exceed 5 Lf and is preferably 1-4 Lf, more preferably about 2
Lf; the concentration of T per 0.5 ml dose of bulk vaccine does not
exceed 10 Lf and is preferably 2.5- 7.5 Lf, more preferably about 5
Lf: the concentration of PT per 0.5 ml dose of bulk vaccine does
not exceed 10 ug and is preferably 2-10 ug, more preferably about 8
ug; the concentration of FHA per 0.5 ml dose of bulk vaccine does
not exceed 10 ug and is preferably 2-10 ug, more preferably about 8
ug; and the concentration of 69 K does not exceed 4 micrograms per
0.5 ml dose of bulk vaccine and is preferably in the range 0.5 ug
to 3 ug per 0.5 ml dose of bulk vaccine. More preferably the
concentration of 69 K in the vaccine is in the range 2 to 3 ug,
more preferably approximately 2.5 ug pertactin per 0.5 ml dose of
bulk vaccine.
[0010] In one aspect the the vaccine compositions of the invention
may, for example, comprise (approximately) PT (2.5 ug), FHA (2.5
ug), 69 K (0.8 ug) per 0.5 ml dose of bulk vaccine
[0011] In a preferred aspect the vaccine compositions of the
invention comprise (approximately) PT (8 ug), FHA (8 ug), 69 K (2.5
ug) per 0.5 ml dose of bulk vaccine.
[0012] In an especially preferred aspect the vaccine compositions
of the invention comprise PT (8 ug), F (8 ug), 69 K (2.5 ug), D (2
Lf) and T (5 Lf) per 0.5 ml dose of bulk vaccine. This was used in
the `dtpa 005` study reported below.
[0013] In another preferred aspect the vaccine composition of the
invention has the amount of the D component increased to 2.5 Lf
[0014] In a further preferred aspect the dtpa tricomponent vaccine
composition is as follows:
[0015] PT 8 .mu.g
[0016] FHA 8 .mu.g
[0017] 69 K 2.5 .mu.g
[0018] diphtheria toxoid>=2 IU
[0019] tetanus toxoid>=20 IU
[0020] Al salts 0.3 mg
[0021] phenoxyethanol 2.5 mg
[0022] This was used in the study in adolescents known as `dtpa
003`, results of which are given below.
[0023] Optionally the PT component may be recombinant (for example
as described in European Patent Applications EP 0 306 318, EP 0 322
533, EP 0 396 964, EP 0 322 115 and EP 0 275 689) or the PT
component may be toxoided, for example as described in EP 0 515
415. See also EP 0 427 462 and WO 91/12020 for the preparation of
pertussis antigens.
[0024] In a further aspect the invention provides a vaccine
composition comprising dtpa (as hereinabove defined) in combination
with one or more additional antigens, particularly an antigen
against hepatitis B (Hep B) (i.e. a Hep B - dtpa vaccine). Such
multivalent vaccines are generally as described in WO 93/24148
except that a low dose of each of D, T, PT, FHA and 69 K as
hereinabove defined is used in the formulation. As described in WO
93/24148 the hepatitis B antigen is preferably hepatitis B surface
antigen.
[0025] The dose of hepatitis B surface antigen will normally be in
the range 5-20 ug per 0.5 ml dose of bulk vaccine.
[0026] The preparation of Hepatitis B surface antigen (HBsAg) is
well documented. See for example, Harford et al in Develop Biol
Standard 54, page 125 (1983), Gregg et al in Biotechnology, 5, page
479 (1987), EP-A- 0 226 846, EP-A-0 299 108 and references
therein.
[0027] As used herein the expression `Hepatitis B surface antigen`
or `HBsAg` includes any HBsAg antigen or fragment thereof
displaying the anticenicity of HBV surface antigen. It will be
understood that in addition to the 226 amino acid sequence of the
HBsAg S antigen (see Tiollais et al, Nature, 317, 489 (1985) and
references therein) HBsAg as herein described may, if desired,
contain all or part of a pre-S sequence as described in the above
references and in EP-A- 0 278 940. HBsAg as herein described can
also refer to variants, for example the `escape mutant` described
in WO 91/14703. In a further aspect the HBsAg may comprise a
protein described as L* in European Patent Application Number 0 414
374, that is to say a protein, the amino acid sequence of which
consists of parts of the amino acid sequence of the hepatitis B
virus large (L) protein (ad or ay subtype), characterised in that
the amino acid sequence of the protein consists of either:
[0028] (a) residues 12-52, followed by residues 133-145, followed
by residues 175-400 of the said L protein; or
[0029] (b) residue 12, followed by residues 14-52, followed by
residues 133-145, followed by residues 175-400 of the said L
protein.
[0030] HBsAg may also refer to polypeptides described in EP 0 198
474 or EP 0 304 578.
[0031] Normally the HBsAg will be in particle form. It may comprise
S protein alone or may be as composite particles, for example
(L*,S) wherein L* is as defined above and S denotes the S-protein
of hepatitis B surface antigen.
[0032] Preferably the HBsAg will be adsorbed on aluminium phosphate
as described in W093/24148. Other antigens may be adsorbed onto
aluminium phosphate or aluminium hydroxide but in some cases
satisfactory results will be obtained only if the other antigen is
adsorbed on aluminium phosphate.
[0033] Other antigens may included in vaccines of the invention to
provide other multivalent vaccines for paediatric, adolescent or
adult use. Suitable said other antigens may, for example, comprise
those known in the art to provide protection against Haemophilus
influenzae b (Hib) and/or polio (IPV) and/or hepatitis A, as
described in WO 93/24148.
[0034] Suitable components for use in such vaccines are already
commercially available and details may be obtained from the World
Health Organisation. For example the IPV component may be the Salk
inactivated polio vaccine. The component affording protection
against Hepatitis A is preferably the product known as `Havrix`
(SmithKline Beecham Biologicals) which is a killed attenuated
vaccine derived from the HM-175 strain of HAV [see `Inactivated
Candidate Vaccines for Hepatitis A` by F. E. Andre, A Hepburn and
E. D'Hondt, Prog Med Virol. Vol 37, pages 72-95 (1990) and the
product monograph `Havrix` published by SmithKline Beecham
Biologicals (1991)]. Conveniently, the Hepatitis B component may
comprise the `S` antigen as already present in the commercial
vaccine `Engerix-B` (SmithKline Beecham Biologicals).
[0035] The amount of antigen in each vaccine dose is selected as an
amount which induces an immunoprotective response without
significant, adverse side effects in typical vaccinees. Such amount
will vary depending on which specific immunogens are employed.
Generally it is expected that each dose will comprise 15-50 ug of
total immunogen. Booster injections may be given. Booster
injections of vaccines according to the invention in subjects
primed with a vaccine comprising whole cell pertussis (Pw) are as
efficacious as in subjects primed with a vaccine comprising
acellular pertussis (Pa).
[0036] In general the vaccine formulations of any aspect of the
invention can be prepared as follows. The required components are
adsorbed onto a suitable adjuvant, most especially aluminium
hydroxide or aluminium phosphate. After allowing time for complete
and stable adsorption of the respective components, the different
components can be combined under appropriate conditions.
[0037] In a preferred aspect of preparing a combined Hepatitis
B-containing vaccine composition according to the invention there
is provided a method which involves mixing aluminium
phosphate-adsorbed HBsAg with one or more aluminium hydroxide or
aluminium phosphate-adsorbed antigens.
[0038] The following examples illustrate the invention:
EXAMPLE 1
Preparation of a dtpa Vaccine Formulation and Study in Adults
[0039] The dtpa vaccine according to the invention was prepared by
standard methodology in accordance with the procedure for
formulating a higher dose DTPa vaccine described in WO
93/24148.
[0040] Results obtained with the vaccine in a clinical study in
adults coded `dtpa 005` are shown in the appended figures, in which
dtpa is used to signify a vaccine according to the invention and
PRN is an abbreviation for pertactin (69 K). The abbreviation dT is
used to signify the standard diphtheria-tetanus vaccine obtainable
from Behringwerke comprising a low dose of diphtheria toxoid and a
higher dose of tetanus toxoid.
[0041] An open, randomised single dose study was carried out in
adults aged 18-45 in Belgium using dtpa formulated as described
above in 60 subjects as compared with dT (Behrin,) in 60
subjects.
[0042] For the dtpa group 28 females were studied (mean age 33
years) and 32 males were studied (mean age 33 years). For the dT
group 32 females were studed (mean age 34 years) and 28 males were
studied (mean age 35 years).
[0043] Excluded were those who had had a diphtheria, tetanus or
pertussis vaccination within the last 10 years or pertussis disease
within the last 5 years.
[0044] Sera were obtained pre and 1 month post vaccination with a
solicited follow-up after 15 days and an unsolicited follow-up
after 30 days.
[0045] Reactogenicity data, antibody responses, anti-PT results,
anti-FHA results and anti-PRN (pertactin) results are shown in the
appended figures.
[0046] In the appended figures, results are also shown for the
monovalent pa vaccine used in the NIH (AAPT) studies reported by
Keitel et al. References to SmithKline Beecham's (SB's) High,
Medium (SB-Med) and Low formulations contain, respectively, PT. (25
ug), FHA (25 ug) and 69 K (8 ug) (High); PT (8 ug), FHA (8 ug) and
69 K (2.5 ug) (Medium); and PT (2.5 ug), FHA (2.5 ug) and 69 K (0.8
ug) (Low).
[0047] The abbreviation `ug` stands for micrograms.
[0048] It may be seen that a dtpa vaccine according to the
invention was safe and immunogenic in adults. Furthermore immune
responses to candidate vaccines of the invention in adults appeared
to be at least several times higher than observed for known higher
dose DTPa vaccines previously administered to US, German and
Italian infants.
EXAMPLE 2
Study in Adolescents (`dtpa 003`)
[0049] An open, randomised single dose study was carried out in
adolescents aged 10-12 in Finland using dtpa formulated as
described above in 120 subjects as compared with dT (Finland) in
120 subjects. The same lot of dtpa vaccine of the invention was
used in both the dtpa 005 and dtpa 003 studies.
[0050] The commercially available (Finland) dT contained:
diphtheria toxoid>=4 IU tetanus toxoid>=40 IU
[0051] For the dtpa group 70 females were studied (mean age 10.9
years) and 49 males were studied (mean age 10.8 years). For the dT
group 62 females were studed (mean age 10.9 years) and 56 males
were studied (mean ace 11.0 years).
[0052] The subjects included in the trial had received up to 4
doses of DTPw within the first 2 years of life.
[0053] Subjects excluded from the study were those who had had D, T
or P vaccination after the second year of Life or a history of
diphtheria, tetanus or pertussis disease.
[0054] Sera were obtained pre and 1 month post vaccination with a
solicited follow-up after 15 days and an unsolicited follow-up
after 30 days.
[0055] Reactogenicity data, antibody responses, anti-PT results,
anti-FHA results and anti-PRN (pertactin) results are shown in the
appended figures.
[0056] It may be seen from the results that a dtpa vaccine
according to the invention was safe and immunogenic in
adolescents.
[0057] Note: In the figures, results relating to the antibody
responses For the study in adults (dtpa 005) and the study in
adolescents (dtpa 003) show the distribution of individual pre- and
post-vaccination anti-diphtheria and anti-tetanus antibody titres
of subjects included in the overall analysis of immunogenicity
(>=0.1 IU/ml being the cut-off determined for protection). Also
given are the geometric mean anti-diphtheria and anti-tetanus
antibody titres in IU/ml.
[0058] The figures for the dtpa 005 and dtpa 003 studies which
illustrate anti-PT, anti-FHA and anti-PRN titers show the vaccine
response rate (in % of the total number of subjects - n -) and
geometric mean antibody titres (GMT, in EU/ml) for the vaccine
components PT, FHA and PRN of subjects included in the overall
analysis of immunogenicity.
EXAMPLE 3
Preparation of a Hep B - dtpa Vaccine
[0059] The formulation was prepared exactly as in Example 5 of
WO93/24148 except that low doses of D, T, PT, FHA and 69 K as
hereinabove defined were used to make up 0.5 ml dose of bulk
vaccine.
[0060] In a preferred composition the amounts of dtpa were
approximately as follows: PT (8 ug), FHA (8 ug), 69 K (2.5 ug), D
(2 Lf) and T (5 Lf) per 0.5 ml dose of bulk vaccine.
[0061] In another preferred composition the amount of D was
increased to 2.5 Lf.
[0062] The amount of hepatitis B surface antigen in the vaccine
composition can vary from 5-20 ug and is typically 10 ug per 0.5 ml
dose of bulk vaccine.
* * * * *